Methyl Esters as Cross-Coupling Electrophiles - ACS Publications

Research Article Cite This: ACS Catal. 2019, 9, 4426−4433

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Methyl Esters as Cross-Coupling Electrophiles: Direct Synthesis of Amide Bonds Yan-Long Zheng and Stephen G. Newman* Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, Ontario K1N 6N5, Canada

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S Supporting Information *

ABSTRACT: Amide bond formation and transition metalcatalyzed cross-coupling are two of the most frequently used chemical reactions in organic synthesis. Recently, an overlap between these two reaction families was identified when Pd and Ni catalysts were demonstrated to cleave the strong C−O bond present in esters via oxidative addition. When simple methyl and ethyl esters are used, this transformation provides a powerful alternative to classical amide bond formations, which commonly feature stoichiometric activating agents. Thus far, few redox-active catalysts have been demonstrated to activate the C(acyl)−O bond of alkyl esters, which makes it difficult to perform informed screening when a challenging reaction needs optimization. We demonstrate that Ni catalysts bearing diverse NHC, phosphine, and nitrogen-containing ligands can all be used to activate methyl esters and enable their use in direct amide bond formation. KEYWORDS: nickel, amide bond formation, cross-coupling, esters

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INTRODUCTION As one of the important functional groups of peptides, pharmaceuticals, agrochemicals, and synthetic materials, amides play a central role in the function of organic molecules.1 As a consequence, the synthesis of amide bonds is one of the most frequently run chemical reactions, usually accomplished by uniting a carboxylic acid and free amine.2 While progress has been made in enabling this reaction to be performed directly,3 the majority of procedures first activate the carboxylic acid moiety as an acid chloride or by using coupling reagents such as EDC, HATU, and PyBOP (Scheme 1A),4 rendering the carbonyl group sufficiently electrophilic for attack by the amine nucleophile. The high need for amidecontaining molecules along with the high cost and waste generated using these common amide bond-forming procedures has led to numerous calls for more efficient methods.5 Esters can provide a promising alternative to carboxylic acids as reaction partners for amide bond formation. Simple methyl and ethyl esters are broadly available, stable, and capable of being carried through multistep synthesis. Alkyl groups are considered a protecting group for carboxylic acids. Further, esters are a useful functional group for α-functionalization and heterocycle syntheses. Due to their nonionizable nature, a different set of challenges is encountered when trying to use esters as electrophiles in amide bond formation. Existing methods primarily rely on activation of the ester by a Lewis acid6 or activation of the amine with aggressive organometallic base,7 with each strategy having significant scope limitations. As a consequence of these limitations, it is common for synthetic chemists to convert esters to amides by first © XXXX American Chemical Society

hydrolyzing to the corresponding carboxylic acid and activation with, e.g., thionyl chloride or peptide coupling reagents prior to amide bond formation.8 In recent years, the development of transition-metalcatalyzed C−O bond activation methods has expanded the diversity and robustness of (pseudo)halide coupling partners that can participate in cross-coupling reactions.9 For instance, esters can be used as a viable alternative to acid chlorides for the synthesis of diverse carbonyl-containing and decarbonylated coupling products.10 This strategy, commonly accomplished with Pd and Ni catalysis, is facilitated by oxidative addition into the C(acyl)−O bond. Early reports in this area used easily activated species such as anhydrides, nitrophenyl esters, enol ether esters, and pyridyl esters.11 More robust phenyl esters were first reported by Itami, Yamaguchi, and coworkers using Ni(0) to catalyze C−H functionalization reactions.12 A number of powerful C−C and C−heteroatomforming reactions were reported afterward using phenyl esters as aryl electrophiles via decarbonylative coupling13 and as acyl electrophiles via a carbonyl-retention mechanistic pathway.14 While phenyl esters are significantly more robust than traditional activated acyl electrophiles such as acid chlorides and anhydrides, they are still nonabundant functional groups that must first by synthesized prior to application. More useful catalytic methods would be able to directly use abundant methyl and ethyl ester starting materials, though the strength Received: February 28, 2019 Revised: April 2, 2019

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DOI: 10.1021/acscatal.9b00884 ACS Catal. 2019, 9, 4426−4433

Research Article

ACS Catalysis

the transformation does not rely on traditional nucleophile− electrophile pairing, both electron-donating and electronwithdrawing functional groups were tolerated on either reaction partner. Similarly, the absence of any basic or acidic additives in the reaction conditions enabled epimerizable stereocenters, acetals, ketals, Michael acceptors, and sites susceptible to attack via SNAr reactions to be untouched. Given the high demand for more efficient amide bondforming reactions and the traditional reliance on acid/base chemistry to functionalize esters, we wished to expand the boundaries of our Ni-catalyzed process. Although our initially reported substrate scope showed over 50 examples of diverse ester and amine reaction partners, many substrates could not be prepared in synthetically useful yields. For example, sterically hindered substrates (e.g., ortho-substituted anilines, benzoates), certain heterocycles (e.g., furans, coumarins), and dialkylamines were found to be problematic. Given that any of the elementary steps of the catalytic cycle could feasibly be turnover limiting, we proposed that different ester−amine pairs may have different optimal conditions. Herein, we describe our efforts in identifying a more diverse subset of ligands that can be used to catalytically activate esters and apply these privileged ligand scaffolds to improve the yields of many challenging amide bond-forming reactions.

Scheme 1. Example Methods for Amide Bond formation

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RESULTS AND DISCUSSION Our originally developed conditions for direct formation of amide bonds from esters and amines used a catalyst formed from mixing Ni(cod)2 with the free N-heterocyclic carbene 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr). With this mixture, methyl benzoate 1 and aniline 2 react to form benzanilide 3 in 83% yield in toluene at 140 °C (Table 1, entry 1). No product is observed in the absence of the Ni (entry 2) or ligand (entry 3), even with stoichiometric base present (entry 4). While this catalyst is promising, both the metal and the ligand are air sensitive and must be weighed inside a glovebox, hindering adoption of the methodology. The airstable, commercially available salt IPr·HCl was found to give a comparable yield to IPr if potassium tert-butoxide (entry 5) or potassium phosphate (entry 6) is used to release the NHC ligand in situ. Moving away from oxygen-sensitive Ni(cod)2 was less successful. In situ reduction of Ni(OAc)2 by stoichiometric Zn10a was inefficient (entry 7), as was the airstable Ni(0) precatalyst Ni[P(OPh)3]4 (entry 8).21 The Ni(II) precatalyst Ni(TMEDA)(o-Tol)Cl 422 provided only 43% yield of product (entry 9). Preformed Ni-NHC complexes23 were similarly inefficient, including the commercial Ni(II) catalysts 5 (entry 10) and 6 (entries 11 and 12), and styrenyl complex 7 (entries 13 and 14).24 These results point to a clear need for more active and more stable alternatives to Ni(cod)2 if methodologies based on this catalyst are to be of broad use.25 Continuing with Ni(cod)2 as the metal source and with the knowledge that NHC salts can be effectively deprotonated in situ, we sought to uncover more viable ligands. While our originally identified ligand IPr (L1) was found to be quite general, there were numerous transformations that gave unsatisfactory yields that we hoped to solve by ligand screening. Using the synthesis of benzanilide 3 as a test reaction, over 60 different ligands were screened (Table S1− S3, Supporting Information)a subset of these are provided in Scheme 2 using 10 mol % ligand if bidentate and 20 mol % ligand if monodentate.26 Most phosphine ligands were entirely ineffective, including XantPhos (L2), CyPAd-Dalphos (L3),

of the corresponding C−O bond makes them more challenging to activate.15 In 2016, Garg and co-workers reported the first amide bond-forming reaction of methyl esters using a Ni(0) catalyst and Al(Ot-Bu)3 as an activating agent (Scheme 1B).16 This seminal report was unfortunately limited to use of methyl 1-naphtholate esters and N-alkyl anilines. Computational studies and control experiments supported a cross-coupling-type mechanism with the Ni catalyst oxidatively adding to the ester C−O bond. Further progress was made toward nontraditional amide bond formation pathways from esters by our group on the use of Pd catalysis17 and by Hu and co-workers in 2017, who reported a nickel-catalyzed coupling of nitroarenes mediated by stoichiometric zinc.18 Their reaction was proposed to proceed by insertion to the C−O bond with an Ni(II) nitrene intermediate. Notably, a large portion of anilines is derived from nitroarenes, making this method highly step economical. Very recently, our group reported that a Ni−NHC catalyst system could enable direct, additive-free synthesis of amides from simple alkyl esters.19 The reaction worked with esters bearing both sp2-(arene)- and sp3-(alkyl)-hybridized carbons at the α position. Furthermore, both aliphatic amines and anilines derivatives could be used. Mechanistically, a cross-couplingtype pathway was proposed and later supported by mechanistic studies by Hong and co-workers, who showed that all three key stepsoxidative addition, proton transfer, and reductive eliminationhave similar transition state energies.20 Since 4427


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ACS Catalysis Table 1. Conditions for Direct Amide Bond Formationa

entry

Ni source

ligands/additives

% yield

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Ni(cod)2 Ni(cod)2 none none Ni(cod)2 Ni(cod)2 Ni(OAc)2 Ni[P(OPh)3]4 4 5 6 6 7 7

IPr (20 mol %) none IPr (20 mol %) KOtBu (20 mol %) IPr·HCl + KOtBu (20 mol %) IPr·HCl (20 mol %) + K3PO4 (1 equiv) IPr (20 mol %) and Zn (1 equiv) IPr (20 mol %) IPr·HCl + KOtBu (20 mol %) none none IPr·HCl + KOtBu (10 mol %) none IPr (10 mol %)

83 0 0 trace 83 73 trace 0 43 8 0 12 53 53

low-yielding reactions. Challenging ester reactants were first targeted. For each ester + amine pair, all of the new ligands (L11−L13 and L20−L25) were tested and compared to L1. The most efficient ligand was identified for each product, and the isolated yield is provided in Scheme 3. For instance, sterically hindered methyl 3-methyl-2-furoate provided amide 8 in 43% yield by 1H NMR under the standard reaction conditions when using IPr as the ligand. Using L22 instead provides 8 in 79% yield (75% after isolation). The Ni/L22 catalyst could be used to make derivatives 9−11 with similar efficiency. A similar observation was found for the synthesis of the isomeric furan derivative fenfuram (12). This fungicide can be manufactured from the corresponding methyl ester using aniline as solvent in the presence of stoichiometric Al as an activating agent.30 With Ni catalysis under our previous standard conditions, only 8% yield was observed. Use of L22 provided 50% isolated yield, and analog 13 could be synthesized in a similarly improved 64% isolated yield. Various ortho-methoxy benzamides have been demonstrated to be inhibitors of cyclooxygenases.31 These electron-rich and sterically hindered amides (14−16) were most efficiently prepared using SIPr L20 as the ligand. The saturated backbone of SIPr gives a slightly increased buried volume relative to IPr,32 which could potentially facilitate a more challenging reductive elimination step. Other ortho-substituted products bearing a fluorine (17) or phenyl (18) group were similarly enabled by the presence of L20. 3-Carboxamido coumarin derivatives such as 19 have been shown as efficient inhibitors against human monoamine oxidases.33 During medicinal chemistry synthesis, they were prepared from the corresponding ester and aniline derivatives by first hydrolyzing the ester in aqueous base and then activating the corresponding acid as an acid chloride or with a diimide coupling reagent. Using L25 as the ligand, carboxamides 19−25 could be directly prepared in 70−90% isolated yields. Notably, even anilines with electron-withdrawing groups could be used, including selective intermolecular coupling with the coumarin ester over potential polymerization to prepare 25. IPr as a ligand was also observed to be poor for performing coupling reactions with αsecondary esters, such as for the formation of proline derivative 26. Here, L20 was observed to give synthetically useful 65% yield, and more nucleophilic anilines with dimethyl (27) and OMe (28) group as well as less nucleophilic anilines with acetyl (29) and COOMe (30) are tolerated. Lastly, pyrrazolebearing amides such as 32 are privileged structures in a number of commercial fungicides. Given the large scale generally required for agrochemical manufacturing, routes to these molecules generally avoid the use of coupling reagents and instead proceed by multistep procedures involving acid chloride intermediates.34 While no ligand could be identified that provided exceptional yields, L24 was found to be superior to IPr, providing 31 and 32 in 40% and 39% yield, respectively. Next, we turned our attention to amine-coupling partners that proved to be challenging using the Ni/IPr catalyst (Scheme 4). Cyclic amines such as morpholine and pyrrolidine are excellent reactants; however, bulky primary amines and noncyclic secondary amines are challenging to couple. For example, adamantan-1-amine provided amide 33 in just 18% yield using L1. Screening of the newly identified ligands enabled the yield to be improved to 91% by the application of L24. This ligand also provided improved yields when using Nmethyl benzylamine and dibenzylamine, giving 34 and 35 in

a

Reactions run at 0.2 M concentration on 0.2 mmol scale. Yield determined by GC-FID of the crude mixture with 1,3,5-trimethoxybenzene as an internal standard.

dppp analog L4, P(o-Tol)3 (L5), SPhos (L6), and PCy3 (L7). Bidentate ligands (L8−L10) showed significant product formation, and dcype (L11) and dcypp (L12) were comparable to L1. One bidentate nitrogen species, L13, also proved to be a viable alternative, demonstrating that three different ligand classes can be used. Next, we focused on varying the steric and electronic environment around the heterocyclic ring and aryl substitutions of L1. Well-known ligands L14−L19 gave low yields of product. In contrast, ligands L20−L25 proved to be viable alternatives to IPr. Notably, several of these ligands are not known to be particularly effective for Ni-catalyzed C−N bond formation. For instance, 2,4,6-tricyclopentylaniline-derived L24 was first synthesized by Plenio in 2014 but has never been reported in any catalytic reactions.27 Pyridine-containing L25, recently reported by Michaelis and co-workers to enable Ni-catalyzed allylation reactions,28 was particularly promising. This ligand has been observed to be bidentate when ligated to many metals,29 making it unique among the other promising NHC ligands identified. With a variety of promising ligands identified as viable in the catalytic synthesis of benzanilide, we explored whether this knowledge could be used to improve previously attempted 4428


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ACS Catalysis Scheme 2. Selected Ligand Evaluation

nucleophile, L24 was most effective, enabling the synthesis of amides 42 and 43 in moderate yield. Synthesis of 44 was more challenging, but L15 showed a drastic improvement over IPr to give a 32% yield. Given the efficient synthesis of amides 25 and 30, which involve selective coupling among two different esters, we next ran competition studies to understand selectivity between different esters (Figure S1). In general, methyl esters bearing α-aryl groups react favorably relative to those bearing α-alkyl groups with the exception of α-benzylic esters which are most reactive. To demonstrate this selectivity, amine 45 was selectively coupled with esters 46 and 47 using L24, affording ester-containing amides 48 and 49 in 79% and 43% yield, respectively (Scheme 5). Substrate 50 underwent a similarly efficient selective reaction at the α-benzyl ester site instead of the α-aryl ester.

53% and 22% yield, respectively. Hindered nicotinamide derivatives were next studied, representing the core scaffold of the fungicide Boscalid. While SIPr (L20) and SIMes (L17) were poor ligands for preparing amide 36, the unsymmetrical mixed analog L23 gave a useful 50% yield. Similar moderate yields were obtained for the preparation of 37−39, suggesting there is a subtle balance of steric factors required when using hindered aniline coupling partners. The most challenging family of amines thus far identified are N-alkyl aniline derivatives. Their reaction with esters is highly thermodynamically uphill, though success was achieved by Garg and coworkers when coupling with naphthalene esters in the presence of stoichiometric Lewis acids.16 Unfortunately, attempts to synthesize N-methyl-N-phenylbenzamide were ineffective with all privileged ligands under additive-free conditions (Table S17, Supporting Information). In contrast, indoline was found to be a good coupling partner, providing amide 40 in near quantitative yield when using L13. Amide 41, which has been demonstrated to inhibit growth human leukemia cells,35 was prepared with similar efficiency. Lastly, amine nucleophiles with remote basic sites were studied, which can potentially compete with the ligand for coordination to the metal center during the catalytic cycle. With pyridylmethyl amine as a

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CONCLUSION In summary, we have greatly expanded the scope of the Nicatalyzed amide bond formation from simple methyl esters and amines. This was accomplished by identifying new ligand families that can enable this transformation. Of the 60 ligands initially tested, 9 were identified as being comparable to our 4429


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ACS Catalysis Scheme 3. Substrate Scope of Challenging Estera

Scheme 4. Substrate Scope of Challenging Aminea

a

General reaction conditions: ester (0.20 mmol), amine (0.24−0.4 mmol), Ni(cod)2 (10 mol %), ligand (20 mol %), t-BuOK (20 mol %), toluene (0.2 M), 140 °C for 16 h. Assay yields of the crude reaction mixture are given in parentheses; isolated yields are reported in bold. b10 mol % ligand.

Scheme 5. Selective Amidation of Esters and Amines

a

General reaction conditions: ester (0.20 mmol), amine (0.24−0.4 mmol), Ni(cod)2 (10 mol %), ligand (20 mol %), t-BuOK (20 mol %), toluene (0.2 M), 140 °C for 16 h. Assay yields of the crude reaction mixture are given in parentheses; isolated yields are reported in bold. bLigand (10 mol %) and t-BuOK (10 mol %) were used.

originally identified ligand, IPr, in the synthesis of benzanilide. Notably, these new ligands are highly diverse, including NHCs, phosphines, and a phenanthroline derivative. With these effective ligands, several challenging coupling reactions can be drastically improved, particularly when using more sterically hindered reactants. In particular, bioactive scaffolds were targeted and yields were improved to provide a synthetically viable alternative to more traditional multistep synthesis. Finally, selective coupling was demonstrated when multiple esters are present, again enabled by the expanded ligand scope. Further efforts are still required to identify a robust, air-stable catalyst. Moreover, the ligands identified still require the use of high reaction temperatures, hindering scale up. With these future developments in mind, the research outlined herein

demonstrates that Ni catalysis has the potential to streamline the synthesis of important amides. Application of these new 4430


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ACS Catalysis

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catalysts to more cross-coupling reactions featuring catalytic activation of methyl esters is underway.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.9b00884. Experimental procedures, characterization of organic molecules, and optimization tables (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Stephen G. Newman: 0000-0003-1949-5069 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support for this work was provided by BASF, the National Science and Engineering Research Council of Canada (NSERC), and the Canada Research Chair program. Martin McLaughlin, Mathias Schelwies, Stephan Zuend, and Roland Götz (BASF) are thanked for helpful discussions. The Canadian Foundation for Innovation (CFI) and the Ontario Ministry of Research, Innovation, & Science are thanked for essential infrastructure.

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